N6,9-disubstituted Adenines: Potent, Selective Antagonists at the A1 Adenosine Receptor

J Med Chem. 1991 Sep;34(9):2877-82. doi: 10.1021/jm00113a029.

Abstract

N6-Substituted 9-methyladenines are potent antagonists of the activation of A1 adenosine receptors. The present study assessed the effect of N6 and N-9 substituents on the binding of adenines to the A1 and A2 receptors, respectively, of rat brain cortex and striatum and also on the antagonism of the A2 receptor mediated stimulation of the adenylate cyclase of PC12 cells by N-ethyladenosine-5'-uronamide. The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl greater than phenyl greater than tetrahydrofuryl greater than ethyl greater than methyl greater than 2-hydroxyethyl. The 9-substituted adenines showed little selectivity for either receptor and the R enantiomer of N6-(1-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the A1 receptor. An N6-cyclopentyl substituent increased potency at the A1 receptor and decreased potency at the A2 receptor, resulting in selectivity for the A1 receptor of up to 39-fold. The N6-cyclopentyl group completely overshadowed the effect of the hydrophobicity of the 9-substituent. A 2-chloro substituent did not alter the potency of an N6-substituted 9-methyladenine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology*
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Purinergic Antagonists*
  • Rats
  • Receptors, Purinergic / metabolism
  • Structure-Activity Relationship

Substances

  • Purinergic Antagonists
  • Receptors, Purinergic
  • Adenylyl Cyclases
  • Adenine